Gabapentin is 1-(aminomethyl)-1-cyclohexaneacetic acid, having the chemical structure: ##STR1##
Gabapentin is used in the treatment of cerebral diseases such as epilepsy. The literature describes many ways of preparing gabapentin from a variety of starting materials. U.S. Pat. No. 4,024,175 describes at least three methods of preparing gabapentin from cyclohexyl-1,1-diacetic acid. Each of these methods results in the formation of gabapentin hydrochloride salt, which may be converted to 1-(aminomethyl)-1-cyclohexaneacetic acid by treatment with a basic ion exchanger and then crystallized from a solvent such as ethanol/ether.
U.S. Pat. No. 4,894,476 specifically discloses an improved method for converting the hydrochloride salt into the free amino acid. This involves pouring a deionized water solution of the salt over an ion exchange column, eluting with deionized water, producing a slurry from the eluate, adding an alcohol to the slurry, centrifuging and drying the slurry to obtain the free amino acid.
Alternative methods for preparing gabapentin have been described that do not proceed via the hydrochloride or any other mineral acid salt. Such methods include those described in U.S. Pat. Nos. 5,132,451, 5,095,148, 5,068,413. Each of these methods involve a cyanic intermediate which is hydrogenated under severe conditions to produce the free amino acid.
These methods are industrially impractical. Those methods comprising ion exchange columns require the use of large amounts of ion exchanger for lengthy periods of time to lower the level of chloride ions to the desired level. The alternative methods involve further more demanding steps.
Commercially available gabapentin is crystalline and exhibits an X-ray diffraction pattern with peaks of 2-theta values at 7.8, 13.3, 15.0, 17.0, 20.4, 21.3, 23.1, 23.6, 25.7, 27.0 and 28.2 degrees. Hereinafter, the commercially available polymorphic form of gabapentin is referred to as polymorph form "II".